Nicotine dependence is thought to underlie the profound public health problems associated with tobacco use. Although nicotine?s effects on the mesoaccumbens DA system likely account for the reinforcing effects of nicotine, it is also known that chronic nicotine exposure produces robust functional tolerance, an effect that may significantly increase the aversive impact of abstinence. The relative contribution of these factors to the maintenance of compulsive tobacco use remains unclear. Animal studies indicate that the temporal pattern of nicotine administration may be a critical factor in the development of certain neural adaptations associated with chronic nicotine exposure. Although this concept is particularly important given the highly regular rates of daily tobacco use exhibited by most smokers, it is unknown how different patterns of nicotine administration influence the ability of this drug to engage the mesoaccumbens DA system. The present proposal is designed to determine how different temporal patterns (continuous, pulsed, or intermittent) of intravenous nicotine administration influence the development of tolerance and/or sensitization. The first aim will determine whether different patterns of identical cumulative nicotine doses will influence the ability of nicotine to stimulate extracellular DA concentrations in the nucleus accumbens. The second aim will assess the effects of different patterns of nicotine administration on subsequent acquisition and maintenance of operant nicotine self-administration. We hypothesized that pulsed nicotine administration will elicit adaptations of the mesoaccumbens DN system distinct from those associated with continuous or intermittent protocols to significantly impact subsequent self-administration behavior.